SAMe is a water soluble physiologically active substance that plays an important role as a methyl group donor in methylation reaction with various transmethylases within the living body, is found in most of cells in the human body, functions as a cofactor of various biochemical reactions, and is a substance that is necessary, for example, for maintenance of cartilage and biosynthesis of brain substances. Studies on functions of SAMe in recent years report curative effects on fatty liver, hyperlipemia, arteriosclerosis, insomnia and the like. SAMe is an important physiologically active substance and is widely used in the Western countries as a therapeutic medication for depression, liver disorder, arthritis and the like, or health foods.
Accordingly, there are strong demands on production and provision of SAMe at low cost with ease, and the known production methods of SAMe include a method of fermentative production using a culture medium containing L-methionine as a precursor (see, for example, Patent Documents 1 to 3 and Non-patent Documents 1 to 7), a method of enzymatically synthesizing SAMe with adenosine 5′-triphosphate (ATP) and L-methionine as substrates using a SAMe synthesizing enzyme (methionine adenosyltransferase), which is isolated and purified from microorganisms, such as a yeast (see, for example, Patent Documents 4 to 5 and Non-patent Documents 7 to 11), and a method of synthesis process (see, for example, Patent Document 6 and Non-patent Document 12).
In the enzymatic synthesis method, SAMe is enzymatically synthesized with adenosine 5′-triphosphate (ATP) and L-methionine as substrates using a SAMe synthesizing enzyme (methionine adenosyltransferase), which is isolated and purified from microorganisms, such as a yeast, and the method has such advantages that SAMe is accumulated in a large amount, and it is not necessary to extract SAMe from the fungus, as compared to the fermentative method, but has various problems, in which preparation of the enzyme is complicated, the resulting enzyme has weak activity, it is necessary to remove a inhibition substance, such as ATP degradation enzyme and ATP as the substrate is considerably expensive, and therefore, the method has not been subjected to practical use.
According to developments of gene engineering in recent years, the enzyme can be conveniently prepared by using cloned SAMe synthesizing enzyme gene (see, for example, Non-patent Documents 6 to 9) to solve the problem in preparation of the enzyme, but other practical problems, such as the use of expensive ATP as the substrate, have not yet been resolved.
Furthermore, SAMe is thermally unstable and is easily decomposed, and as a countermeasure thereto, various attempts have been made for improving the storage stability. For example, such methods are proposed that a composition of SAMe obtained by the aforementioned methods is purified by chromatography or the like, and formed into a salt with sulfuric acid or p-toluenesulfonic acid, a salt with butanedisulfonic acid, or the like, thereby stabilizing SAMe (see, for example, Patent Documents 1 to 3 and 7 to 11), and an additive is added to purified SAMe for stabilization (see, for example, Patent Documents 1 to 3 and 7 to 13), but large amounts of labor and cost are required therefor, and sufficient storage stability cannot be necessarily obtained thereby. Accordingly, it is difficult to provide SAMe, which is important as a therapeutic medication and health foods, at an economical price.
As a method for producing and providing SAMe at an economical price, such a method is reported that a dry yeast containing SAMe is produced by a fermentation method, but SAMe contained in a dry yeast produced cannot have sufficient storage stability (see, for example, Patent Document 14).    [Patent Document 1] JP-B-4-21478    [Patent Document 2] JP-B-6-30607    [Patent Document 3] European Patent No. 1,091,001    [Patent Document 4] JP-A-61-227792    [Patent Document 5] JP-A-2001-169797    [Patent Document 6] U.S. Pat. No. 6,881,837    [Patent Document 7] JP-A-59-51213    [Patent Document 8] JP-A-52-48691    [Patent Document 9] JP-B-1-49274    [Patent Document 10] JP-B-1-49275    [Patent Document 11] JP-T-3-501970    [Patent Document 12] JP-A-60-181095    [Patent Document 13] JP-A-61-91125    [Patent Document 14] JP-A-2005-229812    [Non-patent Document 1] Schlenk F., DePalma R. E., J. Biol. Chem., 229, 1037-1050 (1957)    [Non-patent Document 2] Shiozaki S., et al., Agric. Biol. Chem., 48, 2293-2300 (1984)    [Non-patent Document 3] Shiozaki S., et al., Agric. Biol. Chem., 53, 3269-3274 (1989)    [Non-patent Document 4] Kusakabe H., Kuninaka A., Yoshino H., Agric. Biol. Chem., 38, 1669-1672 (1974)    [Non-patent Document 5] Mudd S H., Cantoni G L., et al., J. Biol. Chem., 231, 481-492 (1958)    [Non-patent Document 6] Shiozaki S., et al., J. Biotechnology., 4, 345-354 (1986)    [Non-patent Document 7] Thomas D., Surdin-Kerjan Y., J. Biol. Chem., 262, 16704-16709 (1987)    [Non-patent Document 8] Markham G. D., et al., J. Biol. Chem., 255, 9082-9092 (1980)    [Non-patent Document 9] Markham D J., DeParisis J., J. Biol. Chem., 259, 14505-14507 (1984)    [Non-patent Document 10] Thomas D., Cherest H., et al., Mol. Cell. Biol., 8, 5132-5139 (1988)    [Non-patent Document 11] Jeongho Park, Junzhe Tai, Charles A. Roessner and A. Ian Scott., Bioorganic & Medical Chemistry, Vol. 4, No. 12, 2179-2185 (1996)    [Non-patent Document 12] Jose R. Mator, Frank M. Raushel, Chi-Huey Wong., Biotechnology and Applied Biochemistry., 9, 39-52 (1987)